Chemotherapy and Atezolizumab for Patients With Extensive Stage Small Cell Lung Cancer (SCLC) With Untreated, Asymptomatic Brain Metastases

• ClinicalTrials.gov Identifier: NCT04610684
• Recruitment Status: Recruiting
• First Posted: October 30, 2020
• Last Update Posted: November 18, 2021
• Sponsor: Jeffrey Clarke
• Collaborators: Genentech, Inc.; Duke University
• Information provided by (Responsible Party): Jeffrey Clarke, Hoosier Cancer Research Network

Study Description

Brief Summary:

This is a single arm, multicenter phase II trial for 60 patients with untreated extensive stage (ES) small cell lung cancer (SCLC) with asymptomatic brain metastases. Subjects will receive 4 cycles of induction treatment with Atezolizumab (1200 mg on Day 1) combined with carboplatin (5-6 AUC on Day 1) and etoposide (80-100 mg/m2 on Days 1-3). Each cycle equals 21 days. After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg on Day 1 of each 3-week cycle. Subjects will receive treatment until disease progression, unacceptable drug-related toxicity, or withdrawal from study for any reason.

Condition or disease	Intervention/treatment	Phase
Small-cell Lung Cancer; Brain Metastases	Drug: Carboplatin; Drug: Etoposide; Drug: Atezolizumab	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Chemotherapy and Atezolizumab for Patients With Extensive Stage Small Cell Lung Cancer (SCLC) With Untreated, Asymptomatic Brain Metastases
• Actual Study Start Date: January 5, 2021
• Estimated Primary Completion Date: May 2022
• Estimated Study Completion Date: May 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Study Treatment Arm; 4 cycles of induction treatment with Atezolizumab (1200 mg on Day 1) combined with carboplatin (5-6 AUC on Day 1) and etoposide (80-100 mg/m2 on Days 1-3). After 4 cycles of induction treatment, subjects will receive atezolizumab maintenance 1200 mg on Day 1 of each 3-week cycle.

Drug: Carboplatin; Carboplatin 5-6 mg/mL/min AUC will be delivered over 30 - 60 minutes intravenously on Day 1 of each 21 day Cycle after completion of atezolizumab. For 4 cycles.; Other Name: paraplatin; Drug: Etoposide; Etoposide 80-100 mg/m2 will be delivered over 60 minutes intravenously on Days 1-3 of each 21 day Cycle after completion of carboplatin (Day 1 only). For 4 cycles.; Other Name: VP-16; Drug: Atezolizumab; Atezolizumab 1200 mg will be delivered over 60 (± 15) minutes intravenously on Day 1 of each 21 day Cycle for 4 cycles then continue as monotherapy maintenance with the same schedule.; Other Name: Imfinzi

Outcome Measures

Primary Outcome Measures :

1. Intracranial progression free survival (iPFS) [ Time Frame: 2 years ]
   iPFS is defined as the time from Day 1 of treatment until the criteria for intracranial disease progression is met as defined by RECIST 1.1 or death as a result of any cause, whichever comes first.

Secondary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: 2 years ]
   ORR will include complete response (CR) + partial response (PR) as determined by RECIST 1.1.
2. Overall Survival (OS) [ Time Frame: 2 years ]
   OS is defined as the time from Day 1 of treatment until death as a result of any cause.
3. Frequency and severity of adverse events [ Time Frame: 2 years ]
   Toxicity will be graded by Common Toxicity Criteria for Adverse Events (CTCAE V5).
4. Progression Free Survival (PFS) [ Time Frame: 2 years ]
   PFS is defined as the time from Day 1 of treatment until the criteria for disease progression (intracranial or extracranial) is met as defined by RECIST 1.1 or death as a result of any cause, whichever comes first.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
2. Age ≥ 18 years with ability and willingness to provide informed consent.
3. ECOG Performance Status of 0-2.
4. Histological confirmation of Small Cell Lung Cancer- Extensive Stage (SCLC) per Veterans Administration Lung Study Group (VALG).
5. At least one untreated asymptomatic brain metastasis that is measurable by RECIST 1.1 that has not been previously irradiated.
6. No prior treatment for metastatic disease. NOTE: A single cycle of chemotherapy (platinum/etoposide) with or without atezolizumab is allowed within 30 days prior to enrollment.
7. Treatment-free for at least 6 months since last chemo/radiotherapy, among those treated (with curative intent) with prior chemo/radiotherapy for limited-stage SCLC.
8. Any prior cancer treatment must be completed at least 6 months prior to registration and the subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to Grade ≤ 1 or baseline. NOTE: a single cycle of chemotherapy (platinum/etoposide) with or without atezolizumab is allowed within 30 days prior to enrollment.
9. A concurrent diagnosis of a separate malignancy is allowed if clinically stable and does not require tumor-directed therapy.

10. Demonstrate adequate organ function as defined in the table below

    • Absolute Neutrophil Count (ANC) ≥ 1.5K/mm3 without GCSF
    • Hemoglobin (Hgb) ≥ 9 g/dL (without transfusion)
    • Calculated creatinine clearance ≥ 50 cc/min OR Serum Cr < 1.5 x institutional ULN
    • Bilirubin ≤ 1.5 × upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) ≤ 2 × ULN without liver metastasis ≤ 5 × ULN with liver metastasis
    • Alanine aminotransferase (ALT) ≤ 2 × ULN without liver metastasis ≤ 5 × ULN with liver metastasis
11. Females of childbearing potential must have a negative serum pregnancy test within 3 days (72 hours) prior to enrollment. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.
12. Females of childbearing potential and males must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 150 days (5 months) after treatment discontinuation.
13. Negative hepatitis B surface antigen (HBsAg) test, negative total hepatitis B core antibody (HBcAb) test, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test. The HBV DNA test will be performed only for patients who have a positive total HBcAb test. Testing required at screening only if results are not known.
14. Negative hepatitis C virus (HCV) antibody test, or positive HCV antibody test followed by a negative HCV RNA test. The HCV RNA test will be performed only for patients who have a positive HCV antibody test. A positive HCV RNA test is sufficient to diagnose active HCV infection in the absence of an HCV antibody test.
15. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures.

Exclusion Criteria:

1. Known active CNS metastases which are symptomatic. CNS metastases are considered asymptomatic if the patient does not require high dose or escalating corticosteroids or anticonvulsant therapy. Steroid dose must be equivalent to 2 mg of dexamethasone or less daily.

   • Prior steroid use as part of an anti-emetic regimen with chemotherapy is allowed.
   • Patients must be on a stable dose of corticosteroid. No tapering or decreasing dose within 7 days of enrollment.
2. Leptomeningeal disease. Discrete dural-based metastases will be allowed without evidence of leptomeningeal disease.
3. Radiation therapy within 14 days prior to Day 1 of Cycle 1 Day 1.
4. Treatment with any investigational drug within 28 days prior to Cycle 1 Day 1.
5. Known auto-immune conditions requiring systemic immune suppression therapy other than prednisone </= 10 mg daily (or equivalent).
6. History of interstitial pneumonitis from any cause.
7. Concurrent severe and/or uncontrolled medical conditions which may compromise participation in the study as assessed by site investigator.
8. Current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment on Cycle 1 Day 1. Patients receiving prophylactic antibiotics (e.g., for prevention of urinary tract infection or chronic obstructive pulmonary disease) are eligible.
9. Current use of medications specified by the protocol as prohibited for administration in combination with the study drugs. This includes patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to Cycle 1 Day 1. Inhaled or topical steroids and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients who are receiving denosumab prior to enrollment must be willing and eligible to receive a bisphosphonate instead.
10. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
11. History of myocardial infarction, NYHA class III or IV congestive heart failure, or unstable angina, cardiac or other vascular stenting, angioplasty, or surgery within 6 months prior to study enrollment.
12. Known history of HIV seropositivity or known acquired immunodeficiency syndrome (AIDS), Testing not required at screening.
13. Requirement for ongoing anticoagulation with heparin, low molecular weight heparin, or other oral anticoagulant (coumadin, DOAC).
14. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently). NOTE: Patients with indwelling catheters (e.g., PleurX®) are allowed.
15. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.
16. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation.
17. History of allergic reactions to carboplatin or etoposide.
18. Intolerance of atezolizumab or other PD-1/PD-L1 axis drug(s), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways, including prior therapy with anti-tumor vaccines or other immune-stimulatory anti-tumor agents.

Contacts and Locations

Contacts

Contact: Jeffrey Clarke, MD; 919-681-4768; jeffrey.clarke@duke.edu

Contact: Ahran Lee; 317-634-5842 ext 14; Alee@hoosiercancer.org

Locations

United States, California

City of Hope; Recruiting

Duarte, California, United States, 91010

Contact: Alanna Muirhead 626-218-0961 amuirhead@coh.org

Principal Investigator: Arya Amini, MD

United States, Illinois

University of Illinis Cancer Center; Recruiting

Chicago, Illinois, United States, 60612

Contact: Erin Keating 312-996-9913 keatin13@uic.edu

Principal Investigator: Sushma Jonna, MD

United States, Indiana

St. Vincent Anderson Regional Hospital; Recruiting

Anderson, Indiana, United States, 46016

Contact: Dee Vester 765-648-4106 Dee.Vester@ascension.org

Principal Investigator: Praveen Ranaganath, MD

United States, Nebraska

Nebraska Methodist Hospital; Recruiting

Omaha, Nebraska, United States, 68114

Contact: Brianna Conyers 402-354-5162 Brianna.Conyers@nmhs.org

Principal Investigator: Timothy Dorius, MD

United States, New Jersey

Summit Health; Recruiting

Berkeley Heights, New Jersey, United States, 07922

Contact: Lorena Farrell 973-436-1752 lfarrell@summithealth.com

Principal Investigator: Karleung Siu, MD

United States, North Carolina

Duke Cancer Institute; Recruiting

Durham, North Carolina, United States, 27710

Contact: Keiana Watkins 919-660-1278 keiana.watkins@duke.edu

Principal Investigator: Jeffrey Clarke, MD

Sponsors and Collaborators

Jeffrey Clarke

Genentech, Inc.

Duke University

Investigators

• Principal Investigator: Jeffrey Clarke, MD; Duke University

More Information

• Responsible Party: Jeffrey Clarke, Sponsor-Investigator, Hoosier Cancer Research Network
• ClinicalTrials.gov Identifier: NCT04610684
• Other Study ID Numbers: HCRN LUN19-427
• First Posted: October 30, 2020
• Last Update Posted: November 18, 2021
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:

Lung Neoplasms; Neoplasm Metastasis; Small Cell Lung Carcinoma; Brain Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neoplastic Processes; Pathologic Processes; Carcinoma, Bronchogenic; Bronchial Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Carboplatin; Etoposide; Atezolizumab; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action